Biliary Obstruction

Background

Disorders of the biliary tract affect a significant portion of the worldwide population, and the overwhelming majority of cases are attributable to cholelithiasis (gallstones). In the United States, 20% of persons older than 65 years have gallstones and 1 million newly diagnosed cases of gallstones are reported each year.

To better understand these disorders, a brief discussion of the normal structure and function of the biliary tree is needed. Bile is the exocrine secretion of the liver and is produced continuously by hepatocytes. It contains cholesterol and waste products, such as bilirubin and bile salts, which aid in the digestion of fats. Half the bile produced runs directly from the liver into the duodenum via a system of ducts, ultimately draining into the common bile duct (CBD). The remaining 50% is stored in the gallbladder. In response to a meal, this bile is released from the gallbladder via the cystic duct, which joins the hepatic ducts from the liver to form the CBD. The CBD courses through the head of the pancreas for approximately 2 cm before passing through the ampulla of Vater into the duodenum.

Pathophysiology

Biliary obstruction refers to the blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine. This can occur at various levels within the biliary system. The major signs and symptoms of biliary obstruction result directly from the failure of bile to reach its proper destination.

The clinical setting of cholestasis or failure of biliary flow may be due to biliary obstruction by mechanical means or by metabolic factors in the hepatic cells. For the sake of simplicity, the primary focus of this article is mechanical causes of biliary obstruction, further separating them into intrahepatic and extrahepatic causes. The discussion of intracellular/metabolic causes of cholestasis is very complex, the pathogenesis of which is not always clearly defined. Therefore, these causes are mentioned but are not discussed in detail.

Intrahepatic cholestasis generally occurs at the level of the hepatocyte or biliary canalicular membrane. Causes include hepatocellular disease (eg, viral hepatitis, drug-induced hepatitis), drug-induced cholestasis, biliary cirrhosis, and alcoholic liver disease. In hepatocellular disease, interference in the 3 major steps of bilirubin metabolism, ie, uptake, conjugation, and excretion, usually occurs. Excretion is the rate-limiting step and is usually impaired to the greatest extent. As a result, conjugated bilirubin predominates in the serum.

Extrahepatic obstruction to the flow of bile may occur within the ducts or secondary to external compression. Overall, gallstones are the most common cause of biliary obstruction. Other causes of blockage within the ducts include malignancy, infection, and biliary cirrhosis. External compression of the ducts may occur secondary to inflammation (eg, pancreatitis) and malignancy. Regardless of the cause, the physical obstruction causes a predominantly conjugated hyperbilirubinemia.

Accumulation of bilirubin in the bloodstream and subsequent deposition in the skin causes jaundice (icterus). Conjunctival icterus is generally a more sensitive sign of hyperbilirubinemia than generalized jaundice. Total serum bilirubin values are normally 0.2-1.2 mg/dL. Jaundice may not be clinically recognizable until levels are at least 3 mg/dL. Urine bilirubin is normally absent. When it is present, only conjugated bilirubin is passed into the urine. This may be evidenced by dark-colored urine seen in patients with obstructive jaundice or jaundice due to hepatocellular injury. However, reagent strips are very sensitive to bilirubin, detecting as little as 0.05 mg/dL. Thus, urine bilirubin may be found before serum bilirubin reaches levels high enough to cause clinical jaundice.

The lack of bilirubin in the intestinal tract is responsible for the pale stools typically associated with biliary obstruction. The cause of itching (pruritus) associated with biliary obstruction is not clear. Some believe it may be related to the accumulation of bile acids in the skin. Others suggest it may be related to the release of endogenous opioids.

Frequency

United States

The incidence of biliary obstruction is approximately 5 cases per 1000 people.

Mortality/Morbidity

The mortality and morbidity of biliary obstruction depend on the cause of the obstruction.

Race

The racial predilection depends on the cause of the biliary obstruction.

• Gallstones are the most common cause of biliary obstruction. Persons of Hispanic origin and Northern Europeans have a higher risk of gallstones compared to people from Asia and Africa.

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• Native Americans (particularly Pima Indians) have an increased incidence of obesity and diabetes within their population and are especially prone to developing gallstones. Pima women have a lifetime chance of developing gallstones as high as 80%.

Sex

The sexual predilection depends on the specific cause of the biliary obstruction.

• Gallstone disease is the most common cause of biliary obstruction. Women are much more likely to develop gallstones than men. By the sixth decade, almost 25% of American women develop gallstones, with as many as 50% of women aged 75 years developing gallstones. This increased risk is likely caused by the effect of estrogen on the liver, causing it to remove more cholesterol from the blood and diverting it into the bile.
• Approximately 20% of men aged 75 years have gallstones, with more complicated disease courses occurring in those who have had cholecystectomies.

Treatment

Medical Care

Treatment of the underlying cause is the objective of the medical treatment of biliary obstruction. Do not subject patients to surgery until the diagnosis is clear. Thus, make every effort to visualize the biliary tree in patients who are jaundiced, with appropriate use of noninvasive and invasive techniques. Importantly, however, a delay in moving on to more invasive therapeutic modalities in a patient who does not initially respond to medical and supportive care increases the risks of an adverse outcome.

• In cases of cholelithiasis in which either the patient refuses surgery or surgical intervention is not appropriate, an attempt to dissolve noncalcified calculi may occasionally be made by the administration of oral bile salts for as long as 2 years.
• • Because gallbladder emptying is an important determinant of stone clearance, normal gallbladder function must first be established via oral cholecystography.

  • Ursodeoxycholic acid (10 mg/kg/d) works to reduce biliary secretion of cholesterol. In turn, this decreases the cholesterol saturation of bile. In 30-40% of patients, this results in the gradual dissolution of cholesterol-containing stones. However, stones may recur within 5 years once the drug is stopped (50% of patients).

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  • Extracorporeal shock-wave lithotripsy may be used as an adjunct to oral dissolution therapy. By increasing the surface-to-volume ratio of the stones, it both enhances dissolution of stones and makes clearing the smaller fragments easier. Contraindications include complications of gallstone disease (eg, cholecystitis, choledocholelithiasis, biliary pancreatitis), pregnancy, and coagulopathy or anticoagulant medications (ie, because of the risk of hematoma formation). Lithotripsy is associated with a 70% recurrence rate for gallstones, is not approved by the US Food and Drug Association, and is restricted to investigational programs only.

• Bile acid–binding resins, cholestyramine (4 g) or colestipol (5 g), dissolved in water or juice 3 times a day may be useful in the symptomatic treatment of pruritus associated with biliary obstruction. However, deficiencies of vitamins A, D, E, and K may occur if steatorrhea is present and can be aggravated by the use of cholestyramine or colestipol. Therefore, include an individualized regimen for replacement of these vitamins as needed in the patient's treatment.

• Antihistamines may be use for the symptomatic treatment of pruritus, particularly as a sedative at night. Their effectiveness is modest. Endogenous opioids have been suggested as possibly playing a role in the development of pruritus of cholestasis. Treatment with parentally administered naloxone and, more recently, nalmefene, has improved pruritus in some patients.

• Rifampin has been suggested as a medical adjunct to the treatment of cholestasis. By decreasing intestinal flora, it slows the conversion of primary to secondary bile salts and may reduce serum bilirubin levels, ALP levels, and pruritus in certain patients.

• Discontinuation of medications that may be causing or exacerbating cholestasis and/or biliary obstruction often leads to full recovery. Similarly, appropriate treatment of infections (eg, viral, bacterial, parasitic) is indicated.

Surgical Care

As with medical care, the need for surgical intervention depends on the cause of biliary obstruction.

• Cholecystectomy is the recommended treatment in cases of symptomatic cholelithiasis because these patients have an increased risk of developing complications.
• • Open cholecystectomy is relatively safe, with a mortality rate of 0.1-0.5 %.

• • Laparoscopic cholecystectomy remains the treatment of choice for symptomatic gallstones, partially because of the shorter recovery period (return to work in an average of 7 d), decreased postoperative discomfort, and improved cosmetic result.

• • Approximately 5% of laparoscopic cases are converted to an open procedure secondary to difficulty visualizing the anatomy or a complication.

• Resectability of neoplastic causes of biliary obstruction varies with respect to the location and extent of the disease. Photodynamic therapy (PDT) has been shown to have good results in the palliative treatment of advanced biliary tract malignancies, particularly when used in conjunction with a biliary stenting procedure. PDT produces localized tissue necrosis by applying a photosensitizing agent, which preferentially accumulates in the tumor tissue, and then exposing the area to laser light, which activates the medication and results in destruction of tumor cells.
• Liver transplantation may be considered in appropriate patients.

Consultations

• Gastroenterologist
• Radiologist
• General surgeon

Diet

Obesity, excess energy intake, and rapid weight loss can lead to stone formation, with potential biliary obstruction as a consequence. Gradual and modest weight reduction may be of value in patients who are at risk.

• Reduce intake of saturated fats.
• High intake of fiber has been linked to a lower risk for gallstones.
• Reduce intake of sugar because a high intake of sugar may be associated with an increased risk of gallstones.

Activity

Regular exercise may reduce the risk of gallstones and gallstone complications.

Medication

Bile acid–binding resins and ursodeoxycholic acid are used to treat cholelithiasis when surgery is refused or is inappropriate. Normal gallbladder function must be established by oral cholecystography findings prior to the initiation of drug therapy.

Drug Category: Gallstone solubilizing agents

Ursodeoxycholic acid (ursodiol) is a naturally occurring bile acid present in small quantities in human bile. Suppresses liver synthesis and secretion of cholesterol. Inhibits intestinal cholesterol absorption.

Drug Name	Ursodiol (Actigall)
Description	Used to treat biliary stasis and dissolve gallstones.
Adult Dose	8-10 mg/kg/d PO divided bid/tid pc until 3 mo after stone is dissolved
Pediatric Dose	10-15 mg/kg/d PO divided tid pc
Contraindications	Documented hypersensitivity; calcified cholesterol, radiopaque or radiolucent bile pigment stones
Interactions	Decreased effect/absorption with aluminum-containing antacids and bile acid–binding resins; estrogens or oral contraceptives may antagonize effect by promoting gallstone formation
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Transaminases (ie, AST, ALT) should be monitored periodically for hepatotoxicity; may cause adverse GI effects, perform US imaging every 6 mo for 1 y to monitor effect, effectiveness dependent on gallstone size/composition, effect unlikely if gallstones are not partially dissolved after 1 y

Drug Category: Narcotic antagonists

Endogenous opioids may effect pruritic development associated with cholestasis. Treatment with narcotic antagonists may attenuate pruritus.

Drug Name	Naloxone (Narcan)
Description	Prevents or reverses opioid effects (eg, hypotension, respiratory depression, sedation, pruritus), possibly by displacing opiates from their receptors.
Adult Dose	0.4 mg IV initially, followed by 0.2 mcg/kg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreased effects of captopril, clonidine, and opioid analgesia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in cardiovascular disease and impaired liver or kidney function; may precipitate withdrawal symptoms in patients dependent on opiates

Drug Category: Antibiotics

Rifampin, in particular, has been suggested as a treatment for cholestasis in certain patients. By reducing intestinal flora, it slows conversion of primary to more toxic secondary bile salts. Has also been shown to decrease serum levels of bilirubin and ALP, perhaps in part contributing to its effectiveness in minimizing associated pruritus.

Drug Name	Rifampin (Rifadin, Rifadin IV, Rimactane)
Description	Inhibits DNA-dependent bacterial by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription.
Adult Dose	5-17 mg/kg/d PO/IV qd; not to exceed 600 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; BP may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea may occur; pseudomembranous colitis has been reported; thrombocytopenia, headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pain in extremities, and generalized numbness have been observed Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have occurred; liver dysfunction may occur and, thus, patients with impaired liver function or taking other hepatotoxic drugs concomitantly should be given rifampin only in cases of necessity and then with caution and under strict medical supervision; in these patients, carefully monitor liver function prior to therapy and then every 2-4 wk during therapy; if signs of hepatocellular damage occur, withdraw; has enzyme induction properties that can enhance the metabolism of endogenous and exogenous substrates, including adrenal hormones, thyroid hormones, vitamin D, and PO hormonal/contraceptive therapy; diabetes may become more difficult to control; may produce a reddish coloration of the urine, sweat, sputum, and tears; soft contact lenses may be permanently stained

Drug Category: Bile acid–binding resins

Inhibit enterohepatic reuptake of intestinal bile salts.

Drug Name	Cholestyramine (Questran)
Description	Acts as a cholesterol-lowering agent. Forms a nonabsorbable complex with bile acids in the intestine, which inhibits enterohepatic reuptake of intestinal bile salts.
Adult Dose	4-6 g PO tid ac (4 g resin/packet or level scoopful); alternatively, 8-12 g PO with breakfast and 4-6 g PO with lunch; not to exceed 24 g/d
Pediatric Dose	240 mg/kg/d PO divided tid ac; not to exceed 8 g/d
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Inhibits absorption of numerous drugs (eg, amiodarone, digoxin, fat-soluble vitamins, folic acid, hydrocortisone, niacin, HMG-CoA inhibitors, thyroid, PO antidiabetic agents, ursodiol, phenobarbital, phosphates, valproate); separating doses by 2-4 h may minimize interaction if drug does not undergo enterohepatic recirculation; monitor serum levels and adjust doses accordingly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Mix powder with water, juice, or milk; discontinue cautiously with concurrent drugs, adjust doses accordingly; causes constipation, heartburn, nausea, and vomiting; caution in PKU when aspartame-containing product is used

Drug Name	Colestipol (Colestid)
Description	Binds bile acids in the intestine, facilitates partial removal of bile acids from enterohepatic circulation, and prevents their reabsorption.
Adult Dose	2-g tab PO qd/bid initially, increase dose by 2 g q1-2mo; not to exceed 16 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; complete biliary obstruction
Interactions	Inhibits absorption of numerous drugs (eg, amiodarone, digoxin, fat-soluble vitamins, folic acid, hydrocortisone, niacin, HMG-CoA inhibitors, thyroid, PO antidiabetic agents, ursodiol, phenobarbital, phosphates, valproate); separating doses by 2-4 h may minimize interaction if drug does not undergo enterohepatic recirculation; monitor serum levels and adjust doses accordingly; conflicting result with digoxin, colestipol preferred over cholestyramine for patients taking digoxin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Swallow tabs whole (ie, do not crush, cut, or chew) one at a time with water; discontinue cautiously with concurrent drugs, adjust doses accordingly; may cause GI obstruction, constipation, or nausea